Individuals with Down syndrome (DS) have a high incidence of speech and swallowing impairments that can have devastating impacts on communicative effectiveness, health, and quality of life. Studies in humans with DS and animal models of DS have reported unique attributes of head and neck nerves and muscles, suggesting that difficulties in communication and swallowing in DS may be due at least in part to peripheral neuromuscular pathologies. However, very little is known about the biological characteristics of these pathologies in DS, how they may manifest and/or interact with anatomic growth during postnatal development and maturation, and how they relate to functional deficits. Additionally, it is unknown if head and neck muscles in DS manifest abnormalities in muscular adaptation to changing demands (neuromuscular plasticity). This lack of knowledge poses considerable barriers in a translational research pathway through which effective treatments for communication and swallowing difficulties may be developed. This proposed research will fill these gaps in knowledge by assessing neuromuscular impairments in head and neck muscles in both Ts65Dn; a trisomic mouse model of DS, and Dp(16)1Yey/+; a mouse model with a duplication of many genes involved in DS. This one-year study has two specific aims. Aim 1: To address the hypothesis that post-natal development in Ts65Dn and Dp(16)1Yey/+ involves abnormalities in muscular adaptations to changing oromotor functional demands, we will quantify mastication rates and changes in muscle myosin heavy chain (MyHC) isoform profiles in response to food consistency modifications after weaning, in juvenile mice versus unaffected sibling controls. We further hypothesize that compared to controls, both juvenile Ts65Dn and Dp(16)1Yey/+ mice will show reduced mastication rates coinciding with atypical MyHC 2b isoform profile shifts in pertinent muscles after food consistency modifications. Aim 2: To test the hypothesis that adult Ts65Dn and Dp(16)1Yey/+ mice have neuromuscular differences within muscles involved in vocalization and mastication, we will examine head and neck neuromuscular function and pathology in the mature mice versus unaffected sibling controls. For this aim we hypothesize that mature Ts65Dn and Dp(16)1Yey/+ mice will show increased neuromuscular junction fragmentation and reduced MyHC 2b levels in head and neck muscles, coinciding with functional deficits in vocalization and mastication. Findings will help provide an understanding of the intrinsic biological attributes of head and neck muscle phenotypes that occur in DS, and will provide insight into phenotypes that may be dynamic through post-natal development. A better understanding of the neuromuscular plasticity and neuromuscular pathologies present in DS will provide substantial momentum to the identification of novel therapeutic targets for deficits unique to this syndrome. It is expected that such knowledge will ultimately permit the development of effective treatments with improved clinical outcomes.